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J. Biol. Chem., Vol. 277, Issue 41, 38133-38140, October 11, 2002
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From the Departments of Recent studies suggest that
adhesion-related kinase (Ark) plays a role in gonadotropin-releasing
hormone (GnRH) neuronal physiology. Ark promotes migration of GnRH
neurons via Rac GTPase and concomitantly suppresses GnRH gene
expression via homeodomain and myocyte enhancer factor-2 (MEF2)
transcription factors. Here, we investigated the signaling cascade
required for Ark inhibition of the GnRH promoter in GT1-7 GnRH neuronal
cells. Ark repression was blocked by the MEK/ERK pathway inhibitor,
PD98059, and dominant negative MEK1 but was unaffected by dominant
negative Ras. Inhibitors of the Rho family GTPases, Clostridium
difficile toxin B (Rho/Rac/Cdc42 inhibitor) and Clostridium
sordellii lethal toxin (Rac/Cdc42 inhibitor), blocked Ark
inhibition of GnRH transcription. Moreover, dominant negative Rac
blunted both Ark activation of ERK and repression of the GnRH promoter,
demonstrating an essential role for Rac in coupling Ark to ERK
activation. Like Ark, a constitutively active mutant of Rac suppressed
GnRH transcription in an ERK-dependent manner. Finally,
Ark-mediated repression was significantly attenuated by a dominant
negative MEF2C, whereas repression induced by constitutively active Rac
was unaffected, indicating that MEF2 proteins are not targets of the
Ark
Adhesion-related Kinase Repression of Gonadotropin-releasing
Hormone Gene Expression Requires Rac Activation of the Extracellular
Signal-regulated Kinase Pathway*
§,§,§,
,§**
Medicine,
¶ Pharmacology, and ** Physiology and Biophysics,
University of Colorado Health Sciences Center, Denver, Colorado 80262, the § Research Service, Veterans Affairs Medical Center,
Denver, Colorado 80220, and the Departments of Immunology and
Cell Biology, Scripps Research Institute,
La Jolla, California 92037
Rac MEK ERK cascade. The data suggest that Ark
suppresses GnRH gene expression via the coordinated activation of a
Rac ERK signaling pathway and a distinct MEF2- dependent mechanism.
*
This work was supported by National Institutes of Health
Grants HD31191-04 (to M. E. W.), HD08667-02 (to M. P. A.), GM44428 (to G. M. B.), by the Veterans Affairs Research Enhancement Award program (to K. A. H. and D. A. L.), and by the Veterans Affairs Merit Review (to M. E. W.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Veterans Affairs
Medical Center, 1055 Clermont St., Box 111H, Denver, CO 80220. Tel.: 303-399-8020 (ext. 3150); Fax: 303-393-5271; E-mail:
margaret.wierman@uchsc.edu.
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